Unlock instant, AI-driven research and patent intelligence for your innovation.

[7,6]-fused bicyclic antidiabetic compounds

a bicyclic antidiabetic and adipose technology, applied in the field of 7 and 6fused bicyclic antidiabetic compounds, can solve the problems of increased and premature morbidity and mortality, inadequate insulin-mediated repression of lipolysis in adipose tissue, and insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle,

Active Publication Date: 2018-11-20
MERCK SHARP & DOHME LLC
View PDF66 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle, and inadequate insulin-mediated repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality.
Patients with Type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy.
Patients with Metabolic Syndrome have an increased risk of developing the macrovascular and microvascular complications that occur with Type 2 diabetes, such as atherosclerosis and coronary heart disease.
Physical exercise and a reduction in dietary intake of calories are the recommended first-line treatment of Type 2 diabetes and of pre-diabetic conditions associated with insulin resistance, however compliance is generally poor.
However, the currently marketed glitazones do not greatly improve lipid metabolism and may negatively effect on the lipid profile.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • [7,6]-fused bicyclic antidiabetic compounds
  • [7,6]-fused bicyclic antidiabetic compounds
  • [7,6]-fused bicyclic antidiabetic compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

(2S,3R)-3-cyclopropyl-3-((R or S)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoic acid

[0609]

[0610]Step A: 1-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl) but-3-en-1-ol To a solution of 2-fluoro-4-(2-methoxypyridin-4-yl)benzaldehyde (1.00 g, 4.32 mmol) in THF (10 mL) was added allylmagnesium bromide (8.65 mL, 8.65 mmol, 1.0 M) dropwise at 0° C. under a N2 atmosphere. The reaction mixture was stirred at 0° C. for 30 min, and at 20° C. for 3 hours. Then the reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by preparative TLC (PE:EtOAc=5:1, v / v) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ=8.23 (d, J=5.2 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.09 (d, J=4...

examples 3 and 4

(2S, 3R)-3-((R or S)-2-(1-(2, 5-bis (trifluoromethyl) benzyl) azetidin-3-yl)-2, 3, 4, 5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoic acid (Example 3: peak 1, faster eluting isomer), and (2S, 3R)-3-((R or S)-2-(1-(2, 5-bis (trifluoromethyl) benzyl) azetidin-3-yl)-2, 3, 4, 5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoic acid (Example 4: peak 2, slower eluting isomer)

[0620]

[0621]Step A: tert-butyl 3-(1-hydroxybut-3-en-1-yl) azetidine-1-carboxylate

[0622]To a solution of tert-butyl 3-formylazetidine-1-carboxylate (2.00 g, 10.8 mmol) in THF (20 mL) was added dropwise allylmagnesium bromide (21.6 mL, 21.6 mmol) at 0° C. under a N2 atmosphere. The reaction mixture was stirred for 30 min at 0° C. and 3 hours at 20° C. (room temperature). Then the reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was ...

example 5

(2S,3R)-3-cyclopropyl-3-((RS)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoic acid

[0633]

[0634]Step A: 4-(5-fluoro-2-methoxypyridin-4-yl)benzaldehyde To a solution of compounds (5-fluoro-2-methoxypyridin-4-yl)boronic acid (800 mg, 4.68 mmol) and 4-bromobenzaldehyde (1.03 g, 5.62 mmol) in THF (10 mL) and water (2.0 mL) were added K2CO3 (1.93 g, 14.0 mmol) and PdCl2(dppf) (342 mg, 0.468 mmol) under a N2 atmosphere. The reaction mixture was stirred at 100° C. for 2 hours, then water (10 mL) was added and the mixture was extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by preparative TLC (PE / EtOAc=5:1) to give the title compound. 1H NMR (400 MHz, CDCl3): δ=10.1 (s, 1H), 8.12 (s, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.77 (d, J=7.2 Hz, 2H), 6.85 (d, J=5.2 Hz, 1H), 3.97 (s, 3H). MS(ESI) ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
enantiomeric excessaaaaaaaaaa
enantiomeric excessaaaaaaaaaa
enantiomeric excessaaaaaaaaaa
Login to View More

Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a U.S. National Phase application under 35 U.S.C. § 371 of Chinese PCT Application No. PCT / CN15 / 086108, filed on Aug. 5, 2015, which claims priority from and the benefit of Chinese PCT Patent Application No. PCT / CN14 / 084034, filed Aug. 8, 2014.BACKGROUND OF THE INVENTION[0002]Diabetes mellitus is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced in the body, however patients have a resistance to the effects of insulin in stimulating glucose and lipid metab...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(United States)
IPC IPC(8): C07D405/14A61K31/444C07D405/04C07D405/10C07D313/08A61K45/06A61K31/335A61K31/397A61K31/4427
CPCC07D405/14A61K31/335C07D405/10C07D405/04C07D313/08A61K45/06A61K31/4427A61K31/444A61K31/397A61K2300/00A61P3/08A61P3/10
Inventor CHOBANIAN, HARRYDEMONG, DUANEPLUMMER, CHRISTOPHER W.FANG, MINGHAIHU, BIN
Owner MERCK SHARP & DOHME LLC